Cigarette smoking is the major known risk factor for the development of chronic obstructive pulmonary disease (COPD); however, the development of airflow obstruction is widely variable among smokers. Severe alpha I-antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD. In subjects without AAT deficiency, familial aggregation for COPD-related phenotypes has been demonstrated, and preliminary evidence for linkage of COPD-related phenotypes to several genomic regions has been obtained by our research group. Participants in the National Emphysema Treatment Trial (NETT) provide an extremely valuable resource to identify novel COPD susceptibility genes. NETT participants provide a group of relatively homogeneous COPD patients, because all subjects have severe emphysema. However, within the NETT population, there are significant differences in the distribution of emphysema and the response to Lung Volume Reduction Surgery (LVRS). We propose to obtain blood samples for DNA extraction from NETT patients; we will use these DNA samples along with the extensive phenotypic assessment of NETT patients to test candidate genes as contributors to COPD susceptibility. Candidate gene polymorphisms, selected from regions of COPD linkage, animal models of COPD, and prior case-control association studies, will be tested between subgroups of NETT patients to determine if these genes contribute to differences in emphysema distribution and clinical response to LVRS. These polymorphisms will also be compared in NETT patients and a population-based control sample to test candidate genes for association with COPD susceptibility. Although previous case-control genetic association studies in COPD have provided inconsistent results, the application of new approaches to test for population stratification, the use of adequate sample sizes, and correction for multiple comparisons will provide a robust study design.